2. JWM Grindelwald 30-01-2008 Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands Johan W. Mouton Pharmacodynamic Indices

3. JWM Grindelwald 30-01-2008 Dosing should be such that the level of antmicrobial activity is associated with a high likelihood of therapeutic success.

4. JWM Grindelwald 30-01-2008 Dose Finding - The Past

5. JWM Grindelwald 30-01-2008 How can PK/PD help here? Potency of a drug (MIC) Exposure to the bug In vivo (PK) Efficacy of the drug

6. JWM Grindelwald 30-01-2008 Lowest concentration with no visible growth after 18 hour incubation MIC.25.5 1 2 4 8 MIC = 2 mg/L X-acin 500 mg PK

7. JWM Grindelwald 30-01-2008 Pharmacokinetic Parameter (and Dose) MIC Thus, we have to: –Establish a relationship between the MIC in vitro and concentrations in vivo (thus, dosing regimens) –Determine which dosing regimens are optimal for Treatment in relation to the MIC

8. JWM Grindelwald 30-01-2008 Any idea where we are today? No idea… may be a mouse? Might be a human, though…

9. JWM Grindelwald 30-01-2008 PK/PD Neutropenic mouse thigh model Various doses and dosing regimens (q1 to q24) Outcome parameter: cfu counts after 24 h Plot PD parameter (AUC, Peak T>MIC) to effect

10. JWM Grindelwald 30-01-2008 K. pneumoniae, imipenem Based on data from Craig

11. JWM Grindelwald 30-01-2008 For K.pneumoniae, there is no clear relation between total daily dose of imipenem and efficacy in an in vivo model of infection

12. JWM Grindelwald 30-01-2008 K. pneumoniae, imipenem Based on data from Craig

13. JWM Grindelwald 30-01-2008 For beta-lactams, there is a direct relation between Time > MIC and efficacy

14. JWM Grindelwald 30-01-2008 Relationship between T>MIC, Peak, AUC and effect of levofloxacin for S. pneumoniae in mice. Each dot represents one mouse / dosingregimen. Based on data from Scaglione & Mouton, 2001, 2003

15. JWM Grindelwald 30-01-2008 levofloxacin ceftazidime Andes IJAA 2002 PK/PD relationship is Class Dependent

16. JWM Grindelwald 30-01-2008 T>MICAUC PenicillinsAminoglycosides CephalosporinsFluoroquinolones CarbapenemsMetronidazole MonobactamsLipopeptides TribactamsKetolides Macrolides Clindamycin Streptogramins GlycopeptidesGlycylcyclines Oxazolidinones Tetracyclines Azoles Relationship PkPd and Effect

17. JWM Grindelwald 30-01-2008 Relationship AUC and effect What has the MIC to do with this? Scaglione et al., AAC 2003

18. JWM Grindelwald 30-01-2008 Andes et al ISHAM 2003 Fluconazole efficacy in mice Dose vs MIC

19. JWM Grindelwald 30-01-2008 MIC PEAK AUC T > MIC AUC and Peak are usually linearly related to Dose Pharmacokinetic parameters : Measures of Exposure

20. JWM Grindelwald 30-01-2008 Pharmacodynamic index (AUC/MIC, Peak/MIC, T>MIC) Pharmacokinetic parameter MIC 'Normalizing pk/pd relationships'

21. JWM Grindelwald 30-01-2008 Andes et al ISHAM 2003

22. JWM Grindelwald 30-01-2008 In vitro effect at fixed concentrations In vivo CT profile dynamic concentrations MIC Response Curve

23. JWM Grindelwald 30-01-2008 Rodriguez-Tudela et al, AAC 2007 Fluconazole efficacy, OPC N=123

24. JWM Grindelwald 30-01-2008 Thus, 2 factors influence the value of the pk/pd index: MIC and its Errors/variation Pharmacokinetics and its variation

25. JWM Grindelwald 30-01-2008 Why is the term pk/pd index used instead of pk/pd parameter? -a ratio (e.g.) of two independent parameters, not a parameter by itself Mouton et al, J Antmicrob Chemother 2005. Available from ISAP site

26. JWM Grindelwald 30-01-2008 The MIC

27. JWM Grindelwald 30-01-2008 The MIC is a result of : kill over time (kill rate) by the antibiotic growth over time (growth rate) for a certain number of micro-organisms (the inoculum) MIC AT STATIC CONCENTRATIONS

28. JWM Grindelwald 30-01-2008 Kahlmeter et al, JAC 2003

29. JWM Grindelwald 30-01-2008 Growth and/or kill rate dependent : –strain, species –medium composition, brand –MH, supplements, ISO –number of bacteria –inoculum –5.10 5 (CLSI) vs 10 5 (BSAC) –temperature (35 o vs 37 o ) –growth phase –CO 2 –etc.

30. JWM Grindelwald 30-01-2008 Mouton, icaac 2000

31. JWM Grindelwald 30-01-2008 A reference MIC method has been described by ISO/CEN Accepted by member States, pending final vote ALL METHODS USED UN THE FUTURE SHOULD BE VALIDATED AGAINST THIS METHOD The method complies with CLSI and EUCAST Several Posters at this ECCMID

32. JWM Grindelwald 30-01-2008 The reproducibility of the MIC is within 2 2-fold dilutions. The variation introduced in the AUC/MIC and Peak/MIC values by the MIC is there for at least 0.5 tot 2 x the pk/pd index value!

33. JWM Grindelwald 30-01-2008 SC= The concentration of antimicrobial at which growth equals kill, i.e. no net growth or kill at a certain point in time =NOT equal to MIC (which includes time) Distinguish between MIC in vitro and in vivo. Mouton & Vinks Clin Pharmacokinet 2005 44:201-10 MIC vs SC (Stationary Concentration)

34. JWM Grindelwald 30-01-2008 MIC MISCONCEPTION: 'Drug is active for a prolonged period of time, and remains above the MIC long enough to…. The SC may be lower or higher than the MIC, depending on its kill kinetics In general the SC is lower, especially for concentration dependent drugs Mouton & Vinks Clin Pharmacokinet 2005 44:201-10

35. JWM Grindelwald 30-01-2008 PHARMACOKINETIC parameters

36. JWM Grindelwald 30-01-2008 Definition :The Area under the Concentration-time curve over 24 hours. Note: ….. It should be stated how the AUC is determined : based on (log) linear trapezoideal rule, based on clearance, or based on microconstants. Dimensions : concentration x time e.g. mg.h/L or  g.h /mL Mouton et al, J Antmicrob Chemother 2005. Available from ISAP site AUC

37. JWM Grindelwald 30-01-2008 AUC 0-24 = 3033 AUC inf = 5100 AUC 0-24 sd = 1361 AUC inf sd =1700 Mg.h/L

38. JWM Grindelwald 30-01-2008 WHICH AUC? AUC 0-24h or AUC  Steady State? (log) trapezodeal rule? Derived ? (A/  +B/  or other)

39. JWM Grindelwald 30-01-2008 Definition : The area under the concentration-time curve over 24 hours in steady state divided by the MIC. …. Note : ….For unbound fraction of the drug, use fAUC/MIC Dimensions : no dimensions Mouton et al, J Antmicrob Chemother 2005 Available from ISAP site AUC/MIC

40. JWM Grindelwald 30-01-2008 Definition :The Area under the inhibitory curve over 24 hours. Note: the AUIC should be reserved for those cases where actual inhibitory titers have been measured and used in the calculations. The AUIC is not equal to the AUC/MIC. See also Flaherty et al, AAC 1988;32(12):1825-29; Hyatt JM et al AAC 1994;38(12):2730-7; Occhipinti DJ et al, AAC 1997;41(11):2511-7. Dimensions : none AUIC Mouton et al, J Antmicrob Chemother 2005 Available from ISAP site

41. JWM Grindelwald 30-01-2008 Peak/MIC Definition : the peak level divided by the MIC. Dimensions : no dimensions. Mouton et al, J Antmicrob Chemother 2005 Available from ISAP site

42. JWM Grindelwald 30-01-2008 Scaglione et al, AAC 2003 WHICH PEAK LEVEL? After the 1st, 2nd or later dose? If more than one compartment, the peak level in compartment 1, 2 or even 3?

43. JWM Grindelwald 30-01-2008 Scaglione et al, AAC 2003

44. JWM Grindelwald 30-01-2008 Time > MIC Definition : the % of time above the MIC over a period of 24 hours. Note : if the period is other than 24 h, this should be stated explicitly. Dimensions : %. Mouton et al, J Antmicrob Chemother 2005 Available from ISAP site

45. JWM Grindelwald 30-01-2008 Variation in methods, definitions Variation in estimation Variation in population

46. JWM Grindelwald 30-01-2008 For all indices : how are they determined how are they calculated what is the error? Only when these questions have been answered do we know the true impact and value of the index.